A widely used COVID-19 drug could fuel the emergence of new SARS-CoV-2 variants, raising concerns that it could prolong and even reignite the pandemic. The drug molnupiravir, manufactured by Merck & Co., aims to kill the virus by inducing mutations in the viral genome. However, a study of viral genomes reported in a new preprint suggests that some people treated with the drug create novel viruses that not only remain viable but also spread.
“It is very clear that viable mutant viruses can survive [molnupiravir treatment] and compete [with existing variants]says virologist William Haseltine, chairman of ACCESS Health International, who has repeatedly raised concerns about the drug. “I think we’re vying for disaster.” However, a Merck spokesman denies that the drug has led to the emergence of widespread variants, and some researchers have downplayed the importance of the mutations caused by molnupiravir. “Right now it’s much ado about nothing,” says Raymond Schinazi, a medicinal chemist at Emory University School of Medicine, noting that the virus associated with SARS-CoV-2, which infects millions of people worldwide, naturally quickly mutated.
Approved in the United Kingdom and United States in late 2021, molnupiravir was the first oral antiviral drug approved to fight COVID-19. Since then, it has been approved in dozens of other countries. In 2022, Merck estimated global sales of the compound at more than $5 billion. Although that’s well below the $18.9 billion achieved in 2022 for Paxlovid, another SARS-CoV-2 oral antiviral drug, molnupiravir remains hugely popular in certain countries.
From the start, however, Haseltine and others were concerned about the drug’s mechanism, which introduces so many mutations into the viral genome that it can no longer reproduce. One concern was that the drug could not only mutate the coronavirus, but also the DNA of people who receive it – a side effect that has not been observed before. Another was that mutated viruses would survive and spread – and perhaps turn out to be more transmissible or virulent than before. Before the U.S. Food and Drug Administration approved the drug, a Merck spokesman called the concern “an interesting hypothetical concern.”
Nevertheless, researchers and citizen scientists from around the world began scanning the SARS-CoV-2 genome sequences deposited in the international GISAID database to look for the types of mutations likely to be caused by molnupiravir. Rather than inducing random changes in the virus’ RNA genome, the drug causes more specific nucleic acid substitutions, with guanine switching to adenine and cytosine to uracil.
A virus hunter, Ryan Hisner, a middle school science and math teacher in Monroe, Indiana, began cataloging suspect variants in August 2022 and quickly identified dozens of sequences that showed clusters of these distinctive substitutions. Hisner voiced his concerns to researchers on Twitter, eventually teaming up with Thomas Peacock, a virologist from Imperial College London. With other colleagues, the pair systematically reviewed more than 13 million SARS-CoV-2 sequences in GISAID and analyzed those with clusters of more than 20 mutations. In a preprint published on January 27, they report that a large subset showed the characteristic substitutions; All date from 2022, after molnupiravir began to be widely available.
The researchers found that these signature clusters were up to 100 times more common in countries where molnupiravir was widely available, including the United States, Australia and the United Kingdom, than in countries like France and Canada where this was not the case . Tracking the dates and locations of the sequences showed that some of the mutant strains were spreading throughout the community. “There’s definitely something happening here,” says Peacock.
Whether the changes result in variants that are more pathogenic or transmissible is unclear, the researchers say. “We can’t come to any conclusions about risk,” says team member Theo Sanderson, a geneticist at the Francis Crick Institute. However, Haseltine compares the danger to keeping a lion as a pet. “Just because it didn’t bite you yesterday doesn’t mean it won’t bite you today,” he says.
The Merck spokesman says the link between the mutations and the drug is unproven. “There is no evidence that an antiviral agent contributed to the emergence of circulating variants,” she says. But the new finding follows two others that could change the risk-benefit calculus for the drug.
In one case, researchers in Australia found evidence that treatment with molnupiravir could lead to new variants in immunocompromised patients. Because these patients’ immune systems have difficulty clearing the virus, viral variants can carry a large number of mutations, potentially causing large leaps in viral behavior that can then be passed on to others. (Researchers have speculated that Omicron and other SARS-CoV-2 variants evolved naturally in immunocompromised people.) By repeat sequencing of the SARS-CoV-2 genomes of nine patients, five of whom received the drug and four If not, the researchers found that molnupiravir-treated subjects harbored an average of 30 new variants each within 10 days of the initial dose, far more than the untreated subjects. “Our study demonstrates that this commonly used antiviral can ‘supercharge’ viral evolution in immunocompromised patients, potentially generating new variants and prolonging the pandemic,” the authors wrote in a December 22, 2022 preprint.
A second report, published on 28 The lancet, suggests that molnupiravir has limited benefits, at least in people who have been vaccinated against COVID-19. The study followed 26,411 vaccinated participants in the UK PANORAMIC clinical trial, about half of whom received the drug. While it reduced the severity of symptoms and improved patients’ recovery times, the researchers found that it did not reduce the incidence of COVID-19-associated hospitalizations or deaths in high-risk adults.
The new British and Australian studies do not prove that molnupiravir causes the emergence of dangerous new SARS-CoV-2 variants, says Ravindra Gupta, clinical microbiologist at the University of Cambridge. But he argues that the drug’s limited benefits suggest it’s no longer worth the risk. “Taken together, these results call into question whether molnupiravir should be used.”